PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking
PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking
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DOI：
10.1074/jbc.ra118.005731
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发表时间：
2019-04
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影响因子：
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通讯作者：
Dyaningtyas Dewi Pamungkas Putri;Takumi Kawasaki;Motoya Murase;T. Sueyoshi;Tomoya Deguchi;D. Ori;S. Suetsugu;T. Kawai
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作者：
Dyaningtyas Dewi Pamungkas Putri;Takumi Kawasaki;Motoya Murase;T. Sueyoshi;Tomoya Deguchi;D. Ori;S. Suetsugu;T. Kawai
先天免疫系统通过产生炎性细胞因子和I型干扰素在病原体感染的初始识别中起重要作用。cGAS是一种用于DNA病毒DNA的细胞质传感器。cGAS与DNA结合诱导cGAMP的产生，cGAMP是与内质网（ER）中的STING相关的第二信使。STING将其细胞分布从ER改变到核周高尔基体，在那里它激活催化IRF3磷酸化的蛋白激酶TBK1。在这里，我们发现STING运输受肌微管蛋白相关蛋白（MTMR）3和MTMR 4的调节，MTMR 3和MTMR 4是蛋白酪氨酸磷酸酶的成员，其将磷脂酰肌醇（PtdIns）的3′位去磷酸化并从PtdIns3，5P2生成PtdIns5P和从PtdIns3P生成PtdIns。我们建立了MTMR3和MTMR4双敲除（DKO）RAW 264.7巨噬细胞，发现它们在干扰素刺激DNA（ISD）刺激和单纯疱疹病毒1型感染后表现出I型干扰素产量增加，并伴随着IRF3磷酸化增强。在DKO细胞中，在ISD刺激后，STING从ER迅速运输到高尔基体。值得注意的是，DKO细胞表现出PtdIns3P阳性的扩大的胞质斑点，并且STING异常地积累在该斑点中。总之，这些结果表明MTMR3和MTMR4调节PtdIns3P的产生，PtdIns3P通过调节STING运输在抑制DNA介导的先天免疫应答中起关键作用。
The innate immune system plays an essential role in initial recognition of pathogen infection by producing inflammatory cytokines and type I interferons. cGAS is a cytoplasmic sensor for DNA derived from DNA viruses. cGAS binding with DNA induces the production of cGAMP, a second messenger that associates with STING in endoplasmic reticulum (ER). STING changes its cellular distribution from ER to perinuclear Golgi, where it activates the protein kinase TBK1 that catalyzes the phosphorylation of IRF3. Here we found that STING trafficking is regulated by myotubularin-related protein (MTMR) 3 and MTMR4, members of protein tyrosine phosphatases that dephosphorylate 3′ position in phosphatidylinositol (PtdIns) and generate PtdIns5P from PtdIns3,5P2 and PtdIns from PtdIns3P. We established MTMR3 and MTMR4 double knockout (DKO) RAW264.7 macrophage cells and found that they exhibited increased type I interferon production after interferon-stimulatory DNA (ISD) stimulation and herpes simplex virus 1 infection concomitant with enhanced IRF3 phosphorylation. In DKO cells, STING rapidly trafficked from ER to Golgi after ISD stimulation. Notably, DKO cells exhibited enlarged cytosolic puncta positive for PtdIns3P and STING was aberrantly accumulated in this puncta. Taken together, these results suggest that MTMR3 and MTMR4 regulate the production of PtdIns3P, which plays a critical role in suppressing DNA-mediated innate immune responses via modulating STING trafficking.